tbuckley/cabot-search huggingface dataset:
TEDOVA/GINECO-OV244b/ENGOT-ov58 trial: Neo-epitope based vaccine OSE2101 alone or in combination with pembrolizumab versus best supportive care (BSC) as maintenance in platinum-sensitive recurrent ovarian cancer with disease control after platinum.
Authors: Alexandra Leary, Elise Deluche, Laure Favier, Xavier Paoletti, Laura Mansi, Olivier Tredan, Lauriane Eberst, Thibault De La Motte Rouge, Florence Joly, Alain Lortholary, Benoit You, Frederik Marmé, Toon Van Gorp, Anne Floquet, Jean-Sebastien Frenel
Journal: Journal of Clinical Oncology (2022)

TPS5614 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A2-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 2021). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information: NCT04713514.
RONC-09. The comparison of dosimetric parameters for predicting radiation-induced cataract in pediatric patients
Authors: Siriphan Leangcharoensap, Kullathorn Thephamongkhol, Teeradon Treechairusame, Nan Suntornpong, Warissara Rongthong
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: The lens dose constraint for pediatric patients was still unknown due to conflicting data of dosimetric parameter. The aim of this study was to compare predictive ability for radiation-induced cataract between the maximum point dose of lens (Lens Dmax) ≥7 Gy, lens mean dose (Lens Dmean) ≥7 Gy, Lens Dmax ≥10 Gy, and Lens Dmean ≥10 Gy. METHOD: Patients 3-18 years received cranial irradiation or radiation therapy at head and neck area with three-dimentional conformal radiation therapy (3DCRT), intensity modulated radiation therapy (IMRT), or volumetric modulated arc therapy (VMAT) between 2010 and 2019 at our institute were included. Patients who have no eye exam before radiation or within 6 months of radiation (baseline) and/or have no follow-up eye examination after complete radiation &amp;gt;6 months (follow-up) were excluded. Receiver operating characteristic (ROC) curves were used to identify the dosimetric parameter of potential predictors and to access their predictability. Univariate and multivariate analyses were performed using cox regression analysis to identify correlation between potential factors and cataract. RESULTS: Sixty-three patients (122 eyes) were analyzed. Cataracts were detected in 14 eyes (11.5%). The median follow-up time was 4 years (range 0.5-10 years). The median time to develop cataract was 2.5 years (range 0.3-7 years). Three (21.4%) patients developed cataract grade ≥3. Lens Dmean ≥10 Gy had highest predictive ability for predicting radiation-induced cataract in pediatric patients. The area under the ROC curve (AUC) were 0.591 for Dmax ≥ 7 Gy, 0.597 for Dmean ≥ 7 Gy, 0.642 for Dmax ≥ 10 Gy, and 0.698 for Dmean ≥ 10 Gy. Univariate analysis showed significant effect of age, diagnosis, and Lens Dmean on cataract formation. On multivariate analysis, cataract remained significantly predicted by diagnosis and Lens Dmean. CONCLUSION: Lens Dmean ≥10 Gy had highest predictive ability for predicting radiation-induced cataract in pediatric patients.
Verapamil for peyronie’s disease: A systematic review and meta-analysis of effectiveness and patient reported outcomes
Authors: A.C. Lavadia, J. Castillo, J. Songco, J.K.J. Kim, J. Delong, R. Virasoro, K. Mccammon, E.M. Sarino, M. Chua
Journal: European Urology (2022)
TBIO-04. Comprehensive analysis of mutational signatures in pediatric cancers
Authors: Venu Thatikonda, S M Ashiqul Islam, Robert J Autry, Barbara C Jones, Susanne Gröbner, Gregor Warsow, Barbara Hutter, Daniel Huebschmann, Stefan Fröhling, Mirjam Blattner-Johnson, David T W Jones, Ludmil B Alexandrov, Stefan M, Pfister, Natalie Jäger
Journal: Neuro-Oncology (2022)

Abstract Analysis of mutational signatures can reveal the underlying molecular processes that have caused the somatic mutations found in genomes. We performed an extensive analysis encompassing mutational signatures of single base substitution and, for the first time, signatures of small insertions/deletions in ~800 whole-genome-sequenced tumor-normal pairs from 25 molecularly defined pediatric cancer types. More than half of this cohort consists of pediatric CNS-tumors (n=416), including high- and low-grade gliomas, ependymomas, and embryonal tumors. These were subsequently compared with COSMIC v.3 signatures to identify overlap with the latest set of known mutational signatures. We identified only a small number of mutational signatures active in pediatric cancers when compared to previously analyzed adult cancers. Amongst these, SBS1 and SBS5 were present in nearly all pediatric tumors analyzed, with a significant correlation of signature activity with age at diagnosis, as expected. Further, we found SBS21 activity in a fraction of high-grade gliomas, which is the result of defective DNA mismatch repair, SBS36 in fractions of ETMR and Group4-medulloblastoma, the result of defective base excision repair, and SBS44 in Group4-medulloblastomas, caused by defective DNA mismatch repair. For these signatures, no consistent genetic alteration was identified. We report a significantly smaller proportion of pediatric tumors which show homologous-recombination repair defect signature SBS3 compared to previously published analyses. Additionally, the previous mutational signature analysis of this cohort based on COSMIC v.2 reference signatures had identified a novel substitution signature (Signature.P1), active in the brain tumors ATRT and ependymoma. Our updated results suggest that Signature.P1 is not a pediatric specific mutational signature, but a treatment-associated signature identified in a small fraction of brain tumors that were annotated as treatment-naïve. This analysis provides a systematic overview of mutational signatures in pediatric cancers, which is relevant for understanding tumor biology and future research in defining biomarkers for treatment response.
Discovery of AMBRA1 and SQSTM1 (p62) as putative biomarkers to identify high risk subsets of patients with cutaneous squamous cell carcinoma.
Authors: Penny Lovat, Michael Alexander, William Cousins, Tom Ewen, Niki Stefanos
Journal: Journal of Clinical Oncology (2022)

e21541 Background: While surgical excision is largely curative, small subsets of patients with cSCC develop metastatic disease for which current AJCC/Brigham and Women’s Hospital staging criteria are unable to reliably identify. There is hence an unmet need for credible prognostic biomarkers to stratify patients based on personalised risk, guide the use of emerging therapeutic intervention for advanced disease and the rationalisation of current/future dermatological healthcare. AMBRA1 and SQSTM1 (p62) play a key role in autophagy and sustained keratinocyte differentiation; two vital processes disrupted in cSCC tumorigenesis, resulting in deregulated cell proliferation and autophagy-mediated tumour cell survival. While AMBRA1 expression is maintained in the normal epidermis its expression is lost in the tumour growth front of cSCCs. Conversely, p62 expression is maintained in basal keratinocytes within the normal epidermis but is lost in the peritumoural epidermis. Collectively these observations suggest tumoural AMBRA1 and peritumoural epidermal p62 expression as biomarkers of cSCC progression. The aim of the present study was to assess the immunohistochemical (IHC) expression of AMBRA1 and p62 in a retrospective cohort of localised or metastatic cSCCs and correlate expression with clinical outcome over 5 years. Methods: Automated IHC analysis of AMBRA1 and p62 expression was performed in a retrospective cohort of well, moderately or poorly differentiated non or metastatic cSCCs. Digital images were annotated prior to H-score expression analysis using optimised cytoplasmic algorithms within Aperio ImageScope software. Results: Receiving Operating Characteristic (ROC) curve analysis revealed an H score of &lt; 20 for peritumoural epidermal p62 and &lt; 60 for expression of AMBRA1 in the cSCC growth front defined cSCCs at high risk of progression while tumours with a p62 H score of ≥ 20 and/or ≥ 60 for AMBRA1 were defined as low risk. Subsequent Kaplan Meier analysis of 51 moderately/poorly differentiated cSCCs demonstrated loss of peritumoural p62 and tumour AMBRA1 expression in 7 tumours correlated with a significantly increased risk of metastasis of 85.7 % compared to 25% for 44 tumours defined as low risk (P &lt; 0.0001, HR 30.07, 95% CI 5.48-165) with an assay specificity of 97%, positive predictive value of 75%, and a negative predictive value of 86%. Conclusions: Overall these data suggest the combined use of tumoural AMBRA1 and peritumoural p62 expression as a putative prognostic biomarker for cSCC metastasis, the future validation of which may provide a valuable stratification tool to guide clinical management, therapeutic intervention and the rationalisation of healthcare resources.
Survival outcomes in metastatic HR-positive, HER2-negative invasive ductal carcinoma compared to invasive lobular carcinoma and mixed ductal/lobular treated with endocrine therapy in combination with CDK4/6 inhibitors, mTOR inhibitor, or PI3K inhibitor.
Authors: Jason A Mouabbi, Akshara Singareeka Raghavendra, Roland L. Bassett, Amy Aida Hassan, Debu Tripathy, Rachel M. Layman
Journal: Journal of Clinical Oncology (2022)

1067 Background: The majority of invasive lobular breast cancers (ILC) are hormone receptor (HR)-positive, HER2-negative and are clinically treated similarly to HR+ HER2-negative invasive ductal cancers (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. It is currently unknown if patients with ILC or mixed ductal/lobular (MDL) histologies derive similar benefits as IDC from endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), mTOR inhibitor everolimus or PI3K inhibitor alpelisib. Methods: We retrospectively searched for patients treated at MD Anderson Cancer Center with a diagnosis of HR+, HER2-negative metastatic breast cancer (MBC) with ET in combination with CDK4/6is, everolimus or alpelisib. Patients were divided into 3 groups based on their histology: ILC, IDC and mixed. We obtained data on demographics, estrogen (ER) and progesterone (PR) receptor status, menopausal status, treatment duration and survival status. The Kaplan-Meier product-limit method was used to compare progression-free survival (PFS) and overall survival (OS) between the three different groups stratified by the treatment received. Results: We identified 2,971 patients (2,432 IDC [82%], 427 ILC [14%], 112 Mixed [4%]) with HR+ HER2-negative MBC treated with ET in combination with CDK4/6is, everolimus and/or alpelisib between 2010 and 2021. Median age was around 50 years in all groups. Around 80% of patients were white, 10% Hispanic and 5% black. Around 55% of patients were post-menopausal, 99% had ER+ and 88% PR+ tumors; 1,895 patients (81% IDC, 15% ILC, 4% mixed) received CDK4/6is, 1,027 (82% IDC, 14% ILC, 4% mixed) received everolimus and 49 (81% IDC, 19% ILC) received alpelisib. PFS and OS were not statistically different between the 3 groups (Table). Conclusions: HR+ HER2-negative MBC patients with IDC, ILC and MDL benefited from ET in combination with CDK4/6is, everolimus or alpelisib similarly with no significant differences in PFS and OS. [Table: see text]
DIPG-28. Indolent<i>H3 K27M</i>-mutant diffuse midline glioma
Authors: Sudarshawn Damodharan, Kristin Bradley, Andrew Stadler, Susan Rebsamen, Jeffrey Helgager, Diane Puccetti
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: H3 K27M-mutant diffuse midline glioma (DMG) is an aggressive central nervous system tumor that is universally fatal with a median survival of 8-12 months after diagnosis. Here we present a patient who was incidentally found to have a lesion within the right thalamus on brain magnetic resonance imaging (MRI). Twelve years later, she was found to have a brain mass within the same area with pathology consistent with an H3 K27M-mutant DMG. CASE DESCRIPTION: A 14-year-old female presented with new onset left-sided numbness and weakness, blurry vision and a right-sided temporal headache. Her past medical history is significant for severe persistent asthma and anoxic brain injury secondary to a cardiopulmonary arrest at 2-years-of-age due to an asthma exacerbation. She has had multiple MRIs of her brain since her initial insult which initially showed the presence of a T2/FLAIR hyper-intense lesion within the right medial thalamus in addition to chronic central nervous system changes. The right thalamic lesion was stable in size between images obtained at 2-years and 4-years of age. Her current physical exam is significant for decreased strength to her left upper and lower extremities. Brain MRI with and without contrast is obtained with partial effacement of the third ventricle due to mass effect from an enlarging mass from the right thalamus. Biopsy of the lesion demonstrated an H3 K27M-mutant DMG, WHO grade IV. Our patient went on to receive palliative radiation therapy with 59.4 Gy over 33 fractions. DISCUSSION: This case illustrates an unusual presentation of an H3 K27M-mutant DMG with an indolent course, diagnosed twelve years after the initial MRI finding. This proposes the possibility of multiple factors playing a role in the oncogenesis of these aggressive tumors and that further research is warranted.
Gene-by-gene analysis in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Shahneen Sandhu, Gerhardt Attard, David Olmos, Eleni Efstathiou, Elena Castro, Dana E. Rathkopf, Matthew Raymond Smith, Guilhem Roubaud, Eric Jay Small, Andrea Juliana Gomes, Marniza Saad, Deniz Tural, Shibu Thomas, Karen Urtishak, Michael Gormley, Gary Mason, Brooke Diorio, George C. Wang, Angela Lopez-Gitlitz, Kim N. Chi
Journal: Journal of Clinical Oncology (2022)

5020 Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]
The predictive values of <i>POTEE</i> mutations for response to immune checkpoint inhibitors in lung adenocarcinoma.
Authors: Yi Yang, Fuqiang Ren, Yuan Wang, Qidong Yang, Lele Zhao, Lin Chen, Yaqin Liu, Mingzhe Xiao
Journal: Journal of Clinical Oncology (2022)

e21110 Background: Precise selection of patients who could benefit from immune checkpoint inhibitors (ICIs)is an important challenge for immunotherapy in lung cancer. POTEE is a member of one primate-specific gene family which have been identified as cancer-related antigens and potential target for immunotherapy of cancer. Here, we investigated the correlation between POTEE mutation and the clinical outcomes of ICIs treatment in lung adenocarcinoma (LUAD). Methods: We merged three independent cohorts from publicly accessible data, the Miao(n = 47), Rizvi (n = 29) and Hellmann (n = 59), to explore the associations between POTEE mutations ( POTEE-mut) and ICIs efficacy. Then we explored the relationship between POTEE mutation and tumor mutational burden (TMB) and PD-L1 expression in the merged cohort. Further, gene set enrichment analyses (GSEA) was used to explore the potential molecular mechanism in The Cancer Genome Atlas (TCGA)-LUAD cohort. Results: In merged cohort, the mutation frequency of POTEE was 7.41% (10 in 135). POTEE-mut group had a significantly higher objective response rate (ORR) (100% vs 27.2%; Fisher’s exact test; P &lt; 0.001) compared to POTEE wildtype group. Kaplan-Meier analysis revealed that POTEE-mut was significantly associated with longer progression-free survival (PFS) (not reached vs 6.1 months, P = 0.001). And at multivariable analysis adjusted by cohort, age, smoking status, line of immunotherapy, PD-L1 expression and TMB, POTEE-mut group showed significant improved PFS with a HR of 0.09(95% CI 0.01-0.71, P = 0.022). Then we explored the association of POTEE alterations with TMB and PD-L1 expression. In merged cohort significantly higher TMB were found in LUAD patient with POTEE mutation (Mann-Whitney U test; p &lt; 0.001). However, there was no association between POTEE mutation and PD-L1 expression. We further explored the potential mechanism of POTTE mutation affecting immunotherapy response using TCGA-LUAD data. GSEA analysis revealed prominent enrichment of signatures related to DNA repair in patients with POTEE mutation (P &lt; 0.001). In detail, four DNA damage response (DDR) pathways, homologous recombination repair (HRR) (NES = 2.108, P &lt; 0.001), translesion DNA synthesis (NES = 1.587, P = 0.01), checkpoint factors (NES = 1.865, P &lt; 0.001) and base excision repair (NES = 1.737, P = 0.002), were all significantly enriched in POTEE-mut tumor. Conclusions: Our data indicated that POTEE mutations were associated with the better response for immunotherapy of LUAD, implying that it can be used as a biomarker for predicting the efficacy of LUAD immunotherapy. POTEE mutation was associated with higher TMB and changed the activity of DNA repair related pathways in LUAD. These may be the underlying mechanisms for POTEE mutations to affect the prognosis of immunotherapy.
The impact of NSCLC disease evolution and treatment on pre- and post-diagnosis weight loss and cachexia designation.
Authors: Puneeth Iyengar, L Anne Gilmore, Santiago Olaechea, Christian Alvarez, Chul Ahn, Rodney E Infante
Journal: Journal of Clinical Oncology (2022)

e24098 Background: While cancer cachexia is associated with increased morbidity/mortality, little is known about longitudinal weight changes and opportunities for intervention pre- and post-diagnosis in this patient population. We therefore aimed to characterize body weight trajectories pre- and post- non-small cell lung cancer (NSCLC) diagnosis in patients without and with cachexia. Methods: Data were retrospectively extracted for each patient pre- and post-diagnosis of NSCLC from inpatient and outpatient visits within the UT Southwestern Medical Center Healthcare System. 3830 participants were screened with a NSCLC diagnosis between May 2005 to December 2019. Of these, 661 patients had a body weight recorded at cancer diagnosis and at least one body weight pre-diagnosis. The primary outcome was weight change over time. Other measures included defining associations between weight change and tumor pathology, stage of disease, and other clinical characteristics. Results: NSCLC patients without cachexia at cancer diagnosis were weight stable up to 12-months pre-diagnosis (+1.0±0.3% body weight; p = 0.01). Weight loss post-diagnosis was driven by stage of disease (stage 1/2: 0.4±0.5% body weight vs. stage 3/4: 4.8±0.9% body weight p = 0.0008) and treatment with chemotherapy (p &lt; 0.0001). NSCLC patients with cachexia at cancer diagnosis lost weight pre-diagnosis (8.8±0.5% body weight; p &lt; 0.0001), with 25% of this weight loss occurring between 6- and 12-months pre-diagnosis. Assessing weight change over 12 months opposed to 6 months resulted in a 32% increase in NSCLC patients with cachexia at cancer diagnosis (p = 0.006). By 12-months post-diagnosis, 62% of surviving late-stage and 45% of early-stage NSCLC patients had met the criteria for cachexia. Patients on average remained free of weight loss for 150±6.4 days or had pre-cachexia for 146±7.2 days prior to transitioning to a more advanced stage of the syndrome. Conclusions: Significant weight loss in NSCLC patients initiated as far back as 12 months prior to a cancer diagnosis as opposed to a shorter 6-month interval currently used to define patients with cachexia. Therefore, detection of earlier weight loss should be prioritized in high-risk NSCLC screening candidates. Finally, advanced NSCLC patients develop cachexia post-diagnosis irrespective of previous weight history, highlighting the impact of treatment iatrogenicity and/or refractory disease on cachexia development.